Biomarkers of basal cell carcinoma resistance to methyl-aminolevulinate photodynamic therapy

Background
Methyl-aminolevulinate photodynamic therapy (MAL-PDT) is an excellent option for the treatment of basal cell carcinoma (BCC). However, up to 25% of cases are resistant to this treatment modality.
Objective
The aim of this study was to identify potential biomarkers of BCC response to MAL-PDT.
Material and methods
Clinical, histological, and immunohistochemical (p53, Ki-67, CD-31, COX2, β-catenin, EGFR, and survivin) variables were analyzed in a retrospective study of consecutive BCC patients treated with MAL-PDT at the San Jorge Hospital, Huesca, Spain between January 2006 and December 2015. To deepen on these markers, the effects on p53 and cyclin D1 expression, in vitro response to MAL-PDT of 2 murine BCC cell lines (ASZ and BSZ), was also evaluated.
Results
The retrospective study examined the response to MAL-PDT of 390 BCCs from 182 patients. The overall clinical response rate was 82.8%, with a mean follow-up time of 35.96 months (SD = 23.46). Immunohistochemistry revealed positive p53 in 84.6% of responders but only 15.4% of nonresponsive tumors (p = 0.011). Tumors with increased peripheral palisading of basal cell islands to immunostaining β-catenin responded poorly to PDT (p = 0.01). In line with our findings in patients, in vitro studies revealed a better response to PDT in the p53-positive ASZ cell line than the p53-negative BSZ cell line (p<0.01).
Multivariate analysis revealed that the following variables were significantly associated with response to PDT: age, nBCC, presence of peritumoral inflammatory infiltrate, and p53 immunopositivity. Patients with positive p53 immunostaining were 68.54 times more likely to achieve cure than p53-negative patients (CI95% 2.94–159.8)
Conclusion
Our finding suggest that certain clinicopathological and immunohistochemical variables, particularly p53 expression, may serve as indicators of BCC response to MAL-PDT, and thus facilitate the selection of patients who are most likely to benefit from this therapy.

背景
氨基酮戊酸甲酯光动力疗法（Methyl-aminolevulinate photodynamic therapy, MAL-PDT）是治疗基底细胞癌（basal cell carcinoma, BCC）的优选方案，但仍有高达25%的病例对该治疗手段产生耐药。
目的
本研究旨在筛选BCC对MAL-PDT应答的潜在生物标志物。
材料与方法
本研究为回顾性研究，纳入2006年1月至2015年12月期间，在西班牙韦斯卡圣乔治医院连续接受MAL-PDT治疗的BCC患者，对其临床、组织学及免疫组化变量（p53、Ki-67、CD31、环氧化酶2（COX2）、β-连环蛋白（β-catenin）、表皮生长因子受体（EGFR）、生存素（survivin））进行分析。为进一步阐明上述标志物的作用机制，本研究还评估了2株鼠源BCC细胞系（ASZ和BSZ）的体外MAL-PDT应答效应，以及p53与细胞周期蛋白D1（cyclin D1）的表达变化。
结果
本回顾性研究共分析了182例患者的390个BCC病灶的MAL-PDT应答情况。总体临床应答率为82.8%，平均随访时间为35.96个月（标准差SD=23.46）。免疫组化结果显示，应答组病灶中84.6%的p53呈阳性，而无应答病灶仅15.4%呈p53阳性（p=0.011）。基底细胞岛外周栅栏状排列伴β-连环蛋白免疫染色增强的病灶对光动力疗法应答较差（p=0.01）。与患者样本中的发现一致，体外实验显示p53阳性的ASZ细胞系比对p53阴性的BSZ细胞系对PDT的应答更佳（p<0.01）。多因素分析显示，年龄、BCC数量、瘤周炎症浸润存在情况及p53免疫阳性与PDT应答显著相关。p53免疫染色阳性患者的治愈几率是p53阴性患者的68.54倍（95%置信区间CI95%：2.94~159.8）。
结论
本研究结果表明，某些临床病理及免疫组化变量，尤其是p53表达，可作为BCC对MAL-PDT应答的预测指标，从而有助于筛选最可能从该疗法中获益的患者。